Traumatic brain injury (TBI) is the most common cause of death and acquired disability among children and young adults in developed countries. Each year in the United States there are approximately 1.6 million cases of TBI, with 300,000 patients requiring hospitalization, and 90,000 patients suffering permanent impairment. Approximately 50% of cases of severe TBI are associated with extracranial injuries; between 5 and 10% of cases with moderate or severe TBI also present with spinal cord injury at cervical level. TBI is a leading cause of combat casualties and modern warfare is associated with a significant increase in blast-induced injuries (Michael-Titus (2009) Clin Lipidology, 4: 343-353). The clinical outcome of these patients is determined not only by the primary brain lesions (laceration, contusion, shearing and axonal stretching), but also by the extent of secondary brain damage caused by the severity of the post-traumatic inflammatory response. Secondary brain damage after traumatic brain injury involves neuroinflammatory mechanisms, mainly dependent on the intracerebral production of cytokines (Chiaretti (2008) Eur. J. Paediatr. Neurol. 12:195-204).
Blast related TBI is of particular concern to the United States Department of Defense because it can lead to permanent neurological injury and deficits. Blast related TBI, often caused by Improvised Explosive Devices (IED), has inflicted significant harm to U.S. and coalition forces (Martin (2008) Am. J. Nurs. 108: 40-47; Warden (2006) J. Head Trauma Rehabil. 21: 398-402; Zeitzer (2008) AAOHN J. 56: 347-53). Even though TBI advancements in body and vehicle armor have improved survival rate from high order explosives, traumatic brain injury remains a significant clinical challenge. Blast-related, closed-head injury is the most common presentation of TBI, and the inflicted damage can result in permanent neurological dysfunction of varying degrees (cognitive and motor deficits, neuropsychiatric and post-traumatic stress disorders, etc.).
Medical treatment of TBI in the unconscious soldier is currently mainly based on emergency, life-saving clinical maneuvers performed by the far forward medical provider including volume resuscitation, protecting airway with sufficient ventilation and oxygenation, and maintenance of vital organ systems in the field of battle, then during transport to the next echelon of care, and after arrival at the higher echelon during the critical care period.
Non-traumatic brain injury such as stroke is the third leading cause of death in the United States behind only heart disease and cancer. About 137,000 Americans die of stroke every year and causes 10% of deaths worldwide. Every year, about 795,000 people in the United States have a stroke. About 610,000 of these are first or new strokes. About 185,000 people who survive a stroke go on to have another. The incidence of stroke increases exponentially from 30 years of age, and etiology varies by age. Advanced age is one of the most significant stroke risk factors. 95% of strokes occur in people age 45 and older, and two-thirds of strokes occur in those over the age of 65. Men are 25% more likely to suffer strokes than women, yet 60% of deaths from stroke occur in women. Some risk factors for stroke apply only to women. Primary among these are pregnancy, childbirth, menopause and the treatment thereof.
Likewise, spinal cord injury (SCI) affects a significant number of patients worldwide. At present, the number of survivors of SCI in the United States is around 250,000 and the annual incidence is approximately 40 cases per million. SCI occurs mainly as a consequence of road accidents, falls and acts of violence and many of the affected are young, as most injuries tend to occur between the ages of 16 and 30. The neurological impairment which follows SCI leads to a significantly reduced quality of life for the patient, and is also associated with a marked personal burden for families (Michael-Titus (2007) PLEFA 77:295-300).
SCI and TBI caused by a penetrating kinetic force (e.g., gunshot wound), mechanical force, or fall, or the blast or shock wave from high order explosives, can cause significant internal traumatic injury to the body and brain. Damage to the brain usually occurs in two stages. The primary phase of injury occurs immediately after the moment of impact causing percussion trauma to the brain tissues and nerve structures. It is often accompanied by disruptions in cerebral blood flow and the cerebrospinal fluid system and is evident in the period immediately following the injury (from minutes to a couple of hours). Vasoconstriction and ischemia occur as a result of neuro-inflammation and edema. The secondary injury is a systemic inflammatory response that accompanies head injury and is associated with chronic inflammation, oxidative stress, and likely permanent damage to individual nerve cells through neural apoptosis and necrosis. This phase continues for days or weeks following injury and can be devastating to the neurologic system or in some cases may result in death of the patient (Bauman (2009) J Neurotrauma 26: 841-860).
At present, the medical management of trauma patients, in particular those suffering a traumatic brain injury, does not include the use of effective anti-inflammatory therapy to address the systemic inflammatory response to trauma or to provide the substrate to begin the repair and rebuilding process of the brain following TBI.
Lipids are a broad group of naturally occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. Lipids generally have poor solubility in water. Lipids are classified as neutral lipids (triglycerides, steroids, and waxes) and polar lipids (phospholipids, glycolipids and lipoproteins). Triglycerides are esters of glycerol and fatty acids (FA). A fatty acid is a carboxylic acid with a long unbranched aliphatic tail (chain), which is either saturated or unsaturated. Fatty acids can be characterized by the length of the chains (2-4 carbon atoms=short-chain fatty acids, 6-12 carbon atoms=medium-chain fatty acids, 16-24 carbon atoms=long-chain fatty acids) and the number of carbon-carbon double bonds (no double bond=saturated, 1 double bond=monounsaturated, 2-3 double bonds polyunsaturated, more than 3 double bonds=highly polyunsaturated).
There are three fatty acid families commonly known as omega-3, 6, and 9 where omega characterizes the position of the first carbon-carbon double bond. The corresponding fatty acid families start with fatty acids having eighteen carbon atoms. The human body can add carbon-carbon double bonds through desaturation and create higher homologues via elongation (Bistrian (2003) JPEN 27, 168-175). All three fatty acid families use the same enzyme system for this purpose and the rate-limiting step is the desaturation by the 6-desaturase. How much of the higher and more unsaturated homologues of the fatty acid families are synthesized depends mainly on the affinity to the enzyme system and the amount supplied in the diet. The affinity of the fatty acids to the elongase-desaturase enzyme system is highest for omega-3, lower for the omega-6 and very low for the omega-9 fatty acids.
Eicosapentanenoic acid (commonly known as EPA; 20:5n-3(ω-3 or omega-3)) and docosahexaenoic acid (commonly known as DHA; 22:6 (ω-3 or omega-3)) are omega-3 essential fatty acids (omega-3 EFA) most often commercially manufactured from refinement and distillation of fish oil or produced commercially from fish oil. Most of the omega-3 fatty acids in fish and other more complex organisms originates in various photosynthetic and heterotrophic microalgae, and concentrates in organisms as it moves up the food chain. Omega-3 fatty acids are commercially manufactured from refinement and distillation of fish oils and from microalgae. DHA is the most abundant essential fatty acid (polyunsaturated fatty acids or PUFAs) in the brain and retina. It comprises 40% of the PUFA in the brain (97% of the omega-3 EFA) and 60% of the PUFA in the retina (93% of the omega-3 EFA). About 50% of the weight of the neuron's plasma membrane is composed of DHA.
While fish oil supplements are ubiquitous in the food marketplace for oral consumption and available in hospitals in the form of liquid enteric feeding (e.g., nasogastric tube or gastric peg tube feeding), there are no omega-3-based fatty acids approved by the United States Food and Drug Administration for intravenous administration or total parenteral nutrition (TPN). Soybean oil based lipid emulsions are the only parenteral nutrition products that have ever been approved in the United States (McClave (2009) J. Parenter. Enteral. Nutr. 33: 277-316) and none are adequate, suitable, or desirable for use in the trauma setting due to their richness in omega-6 fatty acids, which foster a proinflammatory state. Soybean oil is a major source of omega-6 fatty acids which predominate as precursors to arachidonic acid, the highly vasoactive, proinflammatory 2-series prostaglandins and thromboxanes along with the 4-series leukotrienes.
Presently, there are only three commercially available parenteral lipid emulsions containing fish oil derived omega-3 fatty acids in clinical use in Europe and none in the United States. The first product available on the market was Omegaven™ (Fresenius Kabi), a 10% fish oil-in-water emulsion. The second product, Lipoplus™ (B. Braun), is a physical mixture of oils of Medium chain triglycerides or MCT (50%); Soybean (40%) and Fish Oil (10%). The most recent product is SMOFlipid™ (Fresenius Kabi), and is also a physical mixture of oils: soybean oil (30%), MCT oil (30%), Olive oil (25%) and fish oil (15%). Of note, Lipoplus™ and SMOFlipid™ contain 40% and 30% soybean oil, respectively. Soybean oil however, fosters a pro-inflammatory environment. Although Omegaven™ is a pure fish oil emulsion, it has a low-quality fish oil source and the product is a 10% oil-in-water emulsion. Since the early 1960's, Omegaven™ is the only parenteral nutrition product marketed not using a 20% oil-in-water emulsion. Twenty percent oil-in-water emulsions are considered the standard in the industry. Additionally, Omegaven™ requires significantly more volume to be administered because it is half the concentration and contains half the amount of omega-3 fatty acids compared to fish oil that complies with European Pharmacopeia monograph EP1352. Furthermore, the 10% emulsion uses 1.2% (w/v) of egg phospholipids as the emulsifier, the same as found in a 20% formulation. The excess emulsifier forms separate liposomes/micelles that have been shown to interfere with lipoprotein lipase, impairing plasma clearance of lipids, and leading tohypertriglyceridemia (Driscoll (2001) In: Parenteral Nutrition, W.B. Saunders, pp. 35-59).
The present invention provides a stable omega-3 fatty acids based intravenous pharmaceutical composition that would provide a route of administration for optimum bioavailability to be used as an immediate intravenous bolus in an emergency situation (e.g., by emergency medical technicians in an ambulance on the way to a hospital emergency room following an accident, multi-trauma or head injury, on combat situations where the wounded are being transported to a treatment facility) and follow-on intravenous infusion for extended period of time to ameliorate the immediate aftermath of trauma.